01 Oct Keeping up with Ketamine
Q: Recently, I have heard of ketamine (Ketalar®) being used for the treatment of depression or pain. Can ketamine be used for these indications, and are there any concerns for abuse? Does Aegis offer testing for ketamine?
A: At this time, ketamine has not been approved by the Food and Drug Administration (FDA) for use in treatment-resistant depression or chronic pain, despite current off-label uses for both indications. Ongoing clinical trials have revealed rapid and substantial antidepressant effects following ketamine infusions. However, these effects are not sustained over a long period. While studies have demonstrated analgesic effects of ketamine, inconsistencies in dosing regimens and therapeutic responses have led to inconclusive results.
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is FDA approved for the induction and maintenance of anesthesia.1 When used for this indication, ketamine induces a “dissociative anesthesia” characterized by involuntary movement and spontaneous breathing.2 At lower doses, ketamine provides pain relief without producing anesthesia.1 Ketamine is commercially available as an injectable solution. It can also be administered orally, topically, intranasally, and rectally.2,3
Ketamine is a Schedule III controlled substance with a long history of abuse dating back to the 1970s and remains popular as a “club drug” today.4-5 In 2015 Monitoring the Future survey, ketamine abuse was prevalent among 1.4% of 12th graders in the United States.6 Psychostimulant effects of ketamine are dose-dependent and include hallucinations, perceptual disturbances, and dissociative states. Ketamine may be abused through snorting, smoking, injecting or ingesting orally. At high doses, users experience feelings of complete sensory detachment often referred to as “K-hole.” During these sensory distortions, users describe out of body experiences and an altered perception of time and space.4-5 While the psychoactive effects of ketamine last approximately an hour, modifications of the user’s senses, judgment, and coordination may persist for up to 24 hours.5
Clinically, antidepressant effects have been observed in multiple studies following a low dose ketamine infusion. Zarate et al. reported significant improvement over placebo in depression symptoms within 110 minutes. One day after infusion, 71% and 29% met response and remission criteria, respectively. The response was maintained for a week in 35% of subjects.7 Thakurta and colleagues reported significant improvement at 80 minutes post-infusion and found 77% of subjects met response criteria at one-day post-infusion with no subjects meeting remission criteria; the response was maintained for a week in 13% of patients.8 Common side effects noted in these studies were perceptual disturbances, increased blood pressure, euphoria, confusion, headache, and dizziness. While these findings are promising, one limitation is that the antidepressant effects of ketamine have not been sustained long term. Participants typically returned to their baseline depressive state seven days after treatment.7-8 As a result, a recent study focused on extending the duration of ketamine’s effects by administering ketamine three times a week over the course of 12 days. This dosing regimen extended ketamine’s effects to a median of 18 days following the last infusion.9Limitations of ketamine studies for resistant depression included small sample sizes, lack of active comparators, and the potential for abuse in an already susceptible patient population. In 2019, an intranasal formulation of esketamine –
Spravato® – an enantiomer of ketamine, was approved for the treatment of treatment-resistant depression in adults.10 Please note that this medication is administered by a clinician and is not dispensed directly to the patient for self administration. Thus, it may not be listed on a patient’s prescription drug monitoring program history.10
Ketamine’s analgesic effects are mainly attributed to its interaction with NMDA receptors. While many studies have been published, results are complicated by the multiple types of pain evaluated, various doses utilized, side effects limiting therapy and inconsistencies in patient outcomes. An additional complicating factor is the subjective nature of pain, making it impossible to determine a dose-response association when ketamine is administered for this indication.3,11 Despite these limitations, ketamine may have potential to improve analgesia in poor opioid responsiveness, which may be influenced by N-methyl-D-aspartate (NMDA) overactivity. The use of an NMDA antagonist, like ketamine, is advocated by some as a way to improve opioid responsiveness. Several studies have established the efficacy of low-dose ketamine for patients with opioid-resistant pain.12
People with alcohol, opioid, cannabis, and cocaine use disorders have higher rates of depression than the general population. Recently, clinical studies have shown the rapid antidepressant effects of ketamine provide substantial support for its potential use for the treatment of addiction. Research has also shown the effects of ketamine on the expression of drug-related memories. Ketamine has been shown to prolong abstinence in alcohol and heroin dependence and reduce cocaine cravings and self-administration.13 A benefit of ketamine for addiction treatment is that daily dosing is not required. However, studies have limitations, and further randomized controlled trials are needed to confirm the efficacy of ketamine for treating addiction.13
Recently, ketamine clinics have gained popularity and offer treatment of off-labeled indications. The use of ketamine for the treatment of unapproved indications is met with hesitancy as clinical trials have been inconclusive and lack long-term data establishing safety and efficacy. The need for additional studies has been identified.11,14 Despite showing promise in treating depression and pain in clinical trials, ketamine is not recommended as first-line therapy for these indications and requires careful monitoring for adverse effects and substance abuse.
Other potential clinical uses of ketamine recently studied include:
| Potential Clinical Use | Summary of Literature |
| Agitation or excited delirium15 | Ketamine may have a role for agitation management in the prehospital setting. |
| Sedation16 | A continuous ketamine infusion for light sedation was well tolerated with an acceptable safety profile in a cohort of critically ill adults. It may spare the use of traditional sedatives, such as benzodiazepines and propofol, while providing effective sedation. |
| Social anxiety disorder17 | The results of studies for depression and social anxiety have shown ketamine has anxiolytic effects, potentially through the modulation of glutamate. |
| Suicidal ideation18 | A case report of the use of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids which showed a rapid reversal of suicidal ideation and temporary, chronic pain relief. |
At Aegis, samples undergo liquid chromatography/ tandem mass spectrometry (LC/MS-MS) analysis to confirm the presence of ketamine. Aegis laboratories will detect ketamine in samples at a threshold of 1 ng/mL, along with dehydronorketamine and norketamine at a threshold of 5 ng/mL. Providers may test for ketamine by requesting this as an add-on test on the Aegis Laboratory Request form.
NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.
REFERENCES:
1. Ketamine. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc. http://clinicalpharmacology-ip.com. Updated December 20, 2013. Accessed June 10, 2016.
2. Patel PM, Patel HH, Roth DM. General anesthetics and therapeutic gases. In: Brunton LB, Chabner BA, Knollmann BC. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011: 538-539.
3. Blonk M, Koder B, van den Bemt P, Huygen F. Use of oral ketamine in chronic pain management: a review. European Journal of Pain (London, England) [serial online]. May 2010;14(5):466-472. Available from: MEDLINE Complete, Ipswich, MA. Accessed June 15, 2016.
4. Talbert J. Club drugs: coming to a patient near you. The Nurse Practitioner [serial online]. March 13, 2014;39(3):20-25. Available from: MEDLINE Complete, Ipswich, MA. Accessed June 11, 2016.
5. Drug Information: Ketamine. Center for Substance Abuse Research, University of Maryland. http://www.cesar.umd.edu/cesar/drugs/ketamine. asp. Accessed June 11, 2016.
6. Miech RA, Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2016). Monitoring the Future national survey results on drug use, 1975–2015: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan. Available at http://monitoringthefuture.org/pubs.html#monographs.
7. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
8. Thakurta RG, Ray P, Kanji D, Das R, Bisui B, Singh OP. Rapid antidepressant response with ketamine: is it the solution to resistant depression? Indian Journal of Psychological Medicine. 2012;34(1):56-60.
9. Murrough J, Perez A, losifescu D, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry [serial online]. August 15, 2013;74(4):250-256. Available from: MEDLINE Complete, Ipswich, MA. Accessed June 14, 2016.
10. Spravato [package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019.
11. Schoevers R, Chaves T, Balukova S, Rot M, Kortekaas R. Oral ketamine for the treatment of pain and treatment?resistant depression. The British Journal Of Psychiatry: The Journal of Mental Science [serial online]. February 2016;208(2):108?113. Available from: MEDLINE Complete, Ipswich, MA. Accessed June 20, 2016.
12. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012;15(4):474-83.
13. Ivan Ezquerra-Romano I, Lawn W, Krupitsky E, Morgan CJA. Ketamine for the treatment of addiction: evidence and potential mechanisms. Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.01.017.
14. Zhang M, Harris K, Ho R. Is off?label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications. BMC Medical Ethics [serial online]. January 14, 2016;17:4. Available from: MEDLINE Complete, Ipswich, MA. Accessed June 14, 2016.
15. Linder LM, Ross CA, Weant KA. Ketamine for the acute management of excited delirium and agitation in the prehospital setting. Pharmacotherapy. 2018;38(1):139-151.
16. Groetzinger LM, Rivosecchi RM, Bain W, et al. Ketamine infusion for adjunct sedation in mechanically ventilated adults. Pharmacotherapy. 2018;38(2):181-188.
17. Taylor JH, Landeros-Weisenberger A, Coughlin C, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325-333.
18. Bigman D, Kunaparaju S, Bobrin B. Use of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids. BMJ Case Rep. 2017.
